Derivatives of cortisone and hydrocortisone



United States Patent Office 3,026,320 Patented Mar. 20, 1962 3,026,320DERIVATIVES F CORTISONE AND HYDROCORTISONE Carl Djerassi and John A.Zderic, Mexico City, Mexico,

assignors to Syntex, S.A., Mexico City, Mexico, a corporation of MexicoNo Drawing. Filed Nov. 30, 1959, Ser. No. 856,008 Claims priority,application Mexico Nov. 28, 1958 7 Claims. (Cl. 260-23955) Thisinvention relates to novel derivatives of cortisone and hydrocortisone,wherein one of the paired positions C1,2 and C-6,7 constitutes ana-glycol grouping, and the other may also constitute an a-glycolgrouping or may have an unsubstituted single or double carbon-tocarbonbond. Our invention also relates to the aforesaid derivativessubstituted with halogen (fluorine, chlorine or bromine) at C-9a and/ orwith an a-hydroxyl, u-methyl or B-methyl group at 0-16, as well as totheir esters and ketals or acetals. 4

These new compounds which are an object of the present invention, arepotent cortical hormones of anti-inflammatory, thymolytic, glycogenic,eosinopenic and cat-' abolic activity. They are represented by thefollowing general formulas:

Z and Z are members of the group consisting of an unsubstituted singlebond and an unsubstituted double bond;

G is selected from the groups consisting of R and R are members of thegroup consisting of hydrogen and the acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms; R and R are membersselected from the group consisting of hydrogen and of hydrocarbonradicals having up to 8 carbon atoms, saturated or unsaturated, ofstraight, branched, cyclic, mixed straight-cyclic or mixedbranched-cyclic, chain, aliphatic, aromatic or mixed aliphatic-aromatic,and these same hydrocarbon radicals substituted with at least onehydroxyl group, those substituted with an acyl group of a hydrocarboncarboxylic acid having up to 12 carbon atoms, those substituted with analkoxy radical having up to 5 carbon atoms, and those substituted with ahalogen selected from the group consisting of fluorine, chlorine andbromine; R is a bivalent radical of a cyclic hydrocarbon; X is a memberof the group consisting of hydrogen, fluorine, chlorine and bromine, andY is selected from the group consisting of on =0 and The acyl groups arederived from carboxylic acids of 2 to 12 carbon atoms, saturated orunsaturated, of straight, branched, cyclic or mixed straight (branched)-cyclic chain, optionally substituted with functional groups such ashydroxyl, acyloxy (of 1 to 12 carbon atoms), alkoxy (of 1 to 5 carbonatoms) or halogen (F, C1 or Br); typical such esters are, among others,the acetate, propionate, butyrate, hemisuccinate, enanthate, caproate,benzoate, trimethylacetate, phenoxyacetate, phenylpropionate,cyclopentylpropionate and p-chloropropionate.

The methylenedioxy groups characterizing the cyclic ketals and acetalsmay be located at C1,2 and/or C-6,7, and optionally also at C16,17.

By reaction with cyclohexanone there is formed the cyclohexyl-ketalwherein R represents the cyclohexyl groups.

Maximally, a hydrocarbon radical R R or R when substituted can have 20carbon atoms.

Cortisol is used hereinafter for hydrocortisone.

The new compounds of the present invention can be prepared according toa process as illustrated in the reaction diagrams given below. In thesereaction diagrams R is a member 'of the group consisting of n on, n Nand H on, o Acyl R is a member of the group consisting of n on. H H K dn H on, on

R is a member of the group consisting of H CH; 11 and and M is a memberof the group consisting of 0 and R while R, R R R, X, Y, Z and acyl havethe same meaning as explained hereinbefore.

VIIIA VIII B As can be seenfrom the above reaction diagrams, the processaccording to our invention comprises as an essential step the selectivehydroxylation of a double bond other than the A bond of the free21-hydroxyl derivatives or of the 21-esters of a given dehydro-corticalhormone namely the 1-dehydro-, the 6-dehydroand the1,6-bisdehydro-cortisol and -cortisne derivatives, which reaction iscarried out by treating the steroid with osmium tetroxide in mixturewith dioxane, at low temperature for a prolonged period of time,followed by saturation of the mixture with hydrogen sulfide gas,elimination of the solid by filtration, evaporation of the filtrate andsubsequent chromatography of the residue. 7

Instead of treating the intermediate osmic ester with hydrogen sulfide,it may be hydrolyzed by refluxing with sodium sulfite in an adequatesolvent, such as dilute methanol.

Describing now Reaction Diagram I more in detail, the reaction of osmiumtetroxide under the conditions as outlined above upon a l-dehydrocortical hormone of formula =IA in which R is acyl leads to theformation of a 1,2-glycol of the general formula lIAa in which Z is asingle carbon-to-carbon bond.

The same treatment applied to the corresponding starting material IA inwhich R is hydrogen leads to the formation of'the free 2l-hydroxycompound II'IA, in which Z is a single carbon-to-carbon bond. H

Esterification of the hydroxy groups is then elfected by 7 conventionalmethods and leads in both cases to triesters of general formula IVA inwhich Z is again a single bond.

The same reactions carried out with a G-dehydrocorticoid (TC) asstarting material yield first a 6,7-glycol' with a free hydroxyl groupat 0-21 (IIICa) or the corresponding 21-ester EHCa, depending on whetherR in the starting material is hydrogen or acyl, in both of whichformulas Z is a single carbon-to-carbon bond; and esterification ofproducts HCa or 'IICa yields triesters of the formula IVC in which Zagain is a single bond.

("l mone l Thirdly, 1,6-bis-dehydro corticoids of the general for- Amula IB in which R is hydrogen or acyl, used as starting materials inthe above process step afforded a mixture VIIIC of 1,2-glycols offormula -IIAb or II IAb in which Z is a =carbon-to-carbon double bond,and 6,7-glycols of formula IICb or *I-I ICb also with Z being suchdouble bond.

Esterification of the latter compounds yields esters of formulas IVA and'IVC respectively in both of which Z is a double bond.

On the other hand, when using a great excess of osmium tetroxide, in theorder one and a half to two times the amount used in the above describedreaction with 1,6-bisdehydro-corticoids starting materials, andextending the reaction time from a few days, to, for instance, severalweeks, there are obtained l,2,6,7-bis-glycols (1,2,6,7- tetrahydroxyderivatives) having the general formula 'IIB, esterification of whichbis-glycols yields esters of formula IVB.

To form the acetals and ketals, according to the process stepsillustrated in Reaction Diagrams II and III from the'free glycols IHA,'IIIB and IIIC, the latter are caused to react with the correspondingaldehydes or ketones, by a conventional method for the formation ofacetals and ketals starting from OC-gIYCOIS. We preferably employ areaction of the steroid with the carbonyl compound in the presence ofcatalytic amounts of perchloric acid, in the presence or in the absenceof a solvent. Thus we produce, among other ketals, those formed withacetone, methylethylketone, butanone and cyclohexanone, and among otheracetals, those formed with formaldehyde, acetaldehyde, benzaldehyde andfurfural.

More specifically, Reaction Diagram 11 shows that ketalization 0racetalization of new compounds IHAa, =IIIBa and I IICa, in which thepositions at (3-16 are 0ccupied by t H OH: H K or H H CH3 ReactionDiagram HI, on the other hand illustrates the ketalization oracetalization of compounds 'I'IIAb, 1113b and IHCb, containing a freea-hydroxyl group at -16, whereby bis-acetals or bis-ketals at C1,2; C-16,17 (formula VIIA) or C'6,7; C-16,17 (formula VIIC) or triacetals ortriketals at C1,2; C--6,7; 046,17 of formula VIIB are obtained. Thesecompounds VIIA, VI IB and VIIC are esterifiable by conventional methodsat 0-21 to their 21-esters VHIA, VIIIB or VHIC.

The respective double bonds may also be oxidized to u-glycols byreaction with potassium permanganate, although the results of thisreaction are inferior to those of the oxidation'with osmium tetroxide.'In order to adapt our process to an industrial scale, the quantity ofosmium tetroxide required may be reduced to catalytic amounts bycarrying out the hydroxylation step with hydrogen peroxide in thepresence of osmium tetroxide. Furthermore, our process may be employedfor preparing glycols of dehydro compounds having other substituents inaddition to those mentioned hereinbefore, for example, of compoundshaving a fluorine atom at C-6.

In the above-described process, there can be used as starting materialsnovel corticoid intermediates having the general formula in which G isselected from the group consisting of and wherein R, R X, Y, Z and Mhave the same meaning as explained hereinbefore.

These new compounds which are another object of the present inventionare valuable intermediates for the production of the new potent corticalhormones mentioned in the beginning of this application, and for manyother important corticoids.

These new intermediates are produced from the corresponding ring Bsaturated corticoids, by a process illustrated in the following ReactionDiagram 1V in which R is selectedfrom the group consisting of u-OH,a-OAcyl, a-CH and fl-CH- while Acyl, X and Y have the same meaning asexplained hereinbefore:

REACTION DIAGRAM 1v The preferred starting material in this latterprocess is one where Acyl represents the acetyl radical, as for examplethe 21-acetate where R? is CH or 16,21-diacetate of the startingmaterial where R is OAcyl.

Refluxing the A starting corticoids (A) with chloranil in ethyl acetateor xylene produced the A derivation (B) which were transformed to the A-derivatives (C) by a second treatment with chloranil in n-amyl alcohol,or by refluxing with selenium dioxide. These last compounds were alsoobtained directly from the A starting materials (A) by refluxing withchloranil in n-amyl alcohol.

Furthermore, refluxing the known A dienes (D) with chloranil in n-amylalcohol or xylene also gave the corresponding A -triene monoordiacetates (C).

It is understood that other esters of the type previously set forth maybe used instead of the acetates and the A A and A ester compoundsprepared may be conventionally saponified and the resulting freecompounds ketalized and acetalized, or re-esterified with the acylradicals of other hydrocarbon carboxylic acids.

The above process steps are also described as applied to 6-chlorinesubstituted corticoid derivatives in patent application Serial No.753,626, filed August 7, 1958.

The following specific preparations and examples serve to illustrate butare not intended to limit the present invention.

EXAMPLE I A mixture of 5 g. of 160L-In6thyi-COItiS0n ZI-acetatedescribed by Arth et al., in J. Am. Chem. Soc., 80, 3160 (1958), 10 g.of chloranil, 125 cc. of ethyl acetate and 25 cc. of acetic acid wasrefluxed under an atmosphere of nitrogen for 96 hours and poured intoice Water. The organic phase was separated, washed with 10% aqueoussodium hydroxide solution until the washings were colorless, then withwater, dried over anhydrous sodium suitate and the solvent wasevaporated; the residue was chromatographed on neutral alumina, thusgiving 16a-methyl-6-dehydro-cortisone 21-acetate.

A mixture of 3 g. of the above compound, 1 g. of

selenium dioxide, cc. of t-butanol and a few drops of pyridine wasrefluxed for 48 hours, filtered through celite and the solvent wasevaporated. The residue was decolorized by refluxing in acetone solutionwith charcoal, filtered, evaporated to dryness and the crude product waspurified by chromatography on neutral alumina. There was thus obtained16a-methyl-1,6-bis-dehydro-cortisone 21-acetate(16ot-methyl-6-dehydro-prednisone 21- acetate).

7 1 g. of the latter compound was mixed with 50 cc. of dilute methanolicpotassium hydroxide and kept for 1 hour at 0 C. under an atmosphere ofnitrogen, acidified with acetic acid, concentrated to about 10 cc. andpoured into water; the precipitate was collected by filtration, washedwith water, dried and recrystallized from acetonehexane. There was thusobtained the free loot-methyl- 1,6-bis-dehydro-cortisone.

EXAMPLE H The method of the preceding example was applied to I and thereis obtained l6a-methyl-9a-fiuoro-cortisone 21- acetate used as startingmaterial in Example II(r) above.

7 Preparation IV g. of 16fi-methyl-cortisol 21-acetate (I. Am. Chem.

known corticoid compounds I as listed below.

Known Compound I Source New Compound II lone 21-acetate.

Taub et al., J. Am.

Chem. Soc., 80, 3161 (1958). Bernstein et al., I.

m. 16:! -hydroxy 9a fluoro cortisol 16,21-diacetate. Am. Chem. Soc.,

78, 5693 (1956). n. 1fia-hydroxy-Qa-chloro-cortisol 16, do

21-diacetate.

1GB-methyl-S-dehydro-cortlsone 21-acetete and a. ltifi-methyl-cortisone21-acetate- 821251. Soc., 80, 4435 l,G-biS-dehydrO-deriVatiVe.

5 b. 16B-methyl-oortisol 21-acetate do 1(ifi-methyl-(i-dehydro-cortis0121-acetater and 1,G-bis-dehydro-derivative. c.lfia-methyl-cortisol21-acetete Arth et al., J. Am.16a-methyl-S-dehydro-cortisol 21 -acetate and Elhggl. Soc., 80, 3160l,fi-bis-dehydro-derivative.

19 d. lfia-hydroxy-cortisone 16,21-diac- Allen et al., I. Am.16a-hydroxy-fi-dehydro-cortisone 16,21-diaceetate. Elhggi. Soc., 78,1909tate and l,6-bis-dehydr0 derivative.

19 e. lewhydroxveortisol 16,21-diacedo 16a-hydroxy-6-dehydro-cortisol16,21-diacetate tate. and 1,6-bis-dehydro derivative. f.lfifl-methyl-prednisone21-acetate. Taub et al.,loe cit16,8-methyLB-dehydro-prednisone 21-acetate and 1,6-bis-dehydroderivative. 9, lfia-methyl-predmsone21-acetate- Arth etal.,locelt16a-methyl6-dehydro-prednisone 21-acetate and 1,6-bis-dehydroderivative. 1:. lfifl-methyI-prednisolone 21-ace- Taub et a1.,loe cit16,8-methyl-edehydro-prednisolone 2l-acetate t e. and 1,6-bis-dehydroderivative. ,i. lfia-methyl-prednisolone 2l-ace- Arth et al., 100 citlfia-methyl-ti-dehydro-prednisolone 21-ecetate tate. V and1,6-bis-dehydro derivative. 1'. 16a-l1ydroxy-prednis0ne 16,2l-di- U.S.Patent 2,806,043-- lfia-hydroxy-G-dehydro-prednisone 16,21-diacetate.acetate and 1,6-bis-dehydro derivative. k. l6a-hydroxy-prednisolonel6,21- 11.8. Patent2,789,118 16a-hydroxvfi-dehydro-prednisolone16,2l-didiacetate. acetate and 1,6-bis-dehydro derivative. 1.l6a-methyl-9a-fiuoro-prednis0- Arth et al., J. Am;lfiwmethyi-9a-fluoro-6-dehydro-prednisolone 2l-acetate and1,6bis-dehydro derivative.

lfia-hydroxy-ila-fluoro-fi-dehydro-cortisol 16, 21-

diacetate and 1,6-bis-dehydro derivative.

16a-hYdIOXY-Qa-ChlOlO-GflehydIO-OOItiSOl 16, 21-

diacetate and 1,6-bis-dehydro derivative.

0. 1fia-hydroxy-Qa-bromo-cortisol 16, --do16a-hydroxy-Qa-bromo-fi-dehydro-cortisol 16,21

21-diacetate. diacetate and 1,6bis-dehydro derivative.

1). 1604-methyl-9a-bromo-cortis0ne Produced as describedl6a-methyl-Qa-bromoddehydro-cortisone 21- 21-acetate. fbelow inPreparaacetate and 1,6-bis-dehydro derivative.

. ion

g. 16a-methyl-9achlorocortisone Produced as describedl6a-methyl-9a-chloro-6-dehydro-c0rtisone 21- 21-acetate. gelovi I inPreparaacetate and 1,6-bis-dehydro derivative.

r. 16a-methyl-S)a-fiu0ro-cortisone 21- Produced as described16a-methyla-fluoroedehydro-cortisone 21- acetate. belorlvninPreparaacetate and 1,6-bis-dehydro-derivative.

tion s. Arth et al., J'. Am. 16a-methyl-9a-br0mo-6-dehydro-c0rtisol 21-1Sa-methyl-Qa-bromo-cortisol 21- acetate.

16zx-methyl-Qa-chloro-cortisol 21- a etate clGer-methyl-9a-fluoro-cortisol 21- lGfl-Inethyl-9a-chloro-cortisol 21-acetate.

Chem. Soc., 80, 3161 (1958). do

Produced as described below in Preparation IV. do

acetate and 1,6-bis-dehydro derivative.

16a-methyl-9a-ch1oro-6dehydro-cortisol 21-acetate and 1,6bis-dehydroderivative.

1fizz-methyl-Qa-fiuoro-fi-dehydro-cortisol 21-acetate and1,6-bis-dehydro derivative.

1Gfl-methyl-9a-bromo-6-dehydro-cortisol 21-acetate and 1,6-bis-(1ehydroderivative.

1GB-methyl-9a-chloro-fi-dehydro-cortisol 21-aceacetate. tate and1,6-bis-dehydro derivative. 2. ltifi-methyl-Qa-fluoro-cortisol 21- do1BB-methyl-9a-fiuoro-ddehydro-cortisol 21-aceacetate. tate and1,6-bis-dehydro derivative. g1. 16 3-methyl-9a-bromo-cortisone dolfifl-methyl-Qa-bromo-fi-dehydro-eortisone 21- 21-acetate. acetate and1,6-bis-dehydro derivative. 2. 16Bmethyl-9a-chl0ro-cortisone d01SB-methyI-Qa-chloro-fi-dehydro-cortisone 21- 21-acetate acetate and1,6-bis-dehydro derivative. 2. 1Git-methyl-9a-fluoro-c0rtisone 21- do16/Smethyl-Qa-fluoro-fi-dehydro-cortisone 21- acetate andl,6-bis-dehydro derivative.

Preparation I A solution of 1 g. of 16a-methyl-9a-bromo-hydrocortisoneZI-acetate, described by Arth et al., in J. Am.

l6a-methy1=9a-chloro-cortisol 2l-acetate described by Arth et al., suprais treated as described in Preparation I and there is obtained16a-methyl-9a-chloro-cortisone 2iacetate and16a-methyl-9a-chloro-cortisone used as starting material in ExampleII(q) above.

Preparation III l6a-methyl-9a-fiuoro-cortisol 2l-acetate described byArth' et al., supra is treated as described in Preparation Soc., 80,4435 (1958)) was dissolved with slight heating in 125 cc. ofdimethylformamide, cooled, treated with 4.2 cc. of mesyl chloride andheated at C., for half an hour. The cooled mixture was poured into waterand the organic layer was separated, washed with water, dried overanhydrous sodium sulfate and evaporated to dryness. The residue waspurified by recrystallization from acetone-hexane, thus giving 163-methyl-A pregnadien-17u,21-diol-3,20-dione 21-acetate.

7.5 g. of the above diene was mixed with 75 cc. of pure dioxanecontaining 12 cc. of 0.4 N perchloric acid. This mixture was treated inthe dark with .4.2 g. of N- bromoacetamide which was added at roomtemperature in the course of 1 hour. The mixture was stirred for 1 hourfurther, treated with 10% sodium sulfite solution until thestarch-potassium iodide paper no longer showed a blue color. Ice and cc.of chloroform were added and the organic layer was washed with water,sodium bicarbonate solution and water. The extract was then evaporatedunder reduced pressure in a bath kept at a temperature below 25 C. Upontrituration of the residue with acetone and cooling, there was obtainedthe crystalline 16o methyl 9a bromo-cortisol 21 -'acetate.

Concentration of the mother liquors afiorded an additional crop of suchcompound.

A solution of 5.0 g. of l6B-methyl-9a-bromocortisol 21-acetate in 10 cc.of dioxane was slowly added to a mixture of 1.6 g. of anhydrouspotassium acetate and 20 cc. of absolute ethanol which was heated nearto the boiling point. The mixture was refluxed for 45 minutes, cooledand treated with 50 cc. of ice water, with stirring. The precipitate wasfiltered, washed with water and dried. There was thus obtained165-methyl-9B,llfioxido-A pregnen-17a,2l-dio1-3,20-dione 21-acetate.

4 g. of the above epoxide was dissolved in 40 cc. of pure chloroform,cooled to C., and treated at this temperature and under stirring with 8cc. of a 0.5 N solution of dry hydrogen chloride in chloroform. Themixture was stirred at 0 C. for 1 hour and then water was added and thechloroform layer was washed with water, 5% sodium carbonate solution andwater, dried over anhydrous sodium sulfate and evaporated to drynessunder reduced pressure. The residue crystallized from acetone, thusgiving 16i3-methyl-9a-chloro-cortisol- Zl-acetate.

In a polyethylene flask fitted with a magnetic stirrer there wasdissolved 5 g. of 16,8-methyl-913Jlfi-oxido-M-pregnen-17a,21-diol-3,20-dione 21-acetate, obtained as described above,in 80 cc. of pure chloroform and cooled to 0 C.; while the temperaturewas kept below 0 C., and under continuous stirring there was then added0.8 g. of anhydrous hydrogen fluoride, in the course of 20 minutes. Thestirring was continued for 2 hours further and the mixture was thenneutralized by the cautious addition of an aqueous suspension of sodiumbicarbonate.

The mixture was transferred to a separatory funnel, washed with waterand the organic layer was concentrated under reduced pressure until abulky crystalline precipitate formed. After cooling, the precipitate wascollected, redissolved in 20 cc. of hot ethyl acetate, filtered from theinsoluble material and cooled. There was thus obtained16fi-methyl-9u-fiuoro-cortisol 21-acetate.

Oxidation of the ll-hydroxyl group with chromium trioxide as describedabove in Preparation I, II and III for the 16a-methyl series gave thecorresponding keto analogs:

16B-methyl-9a-bromo-eortisone acetate 165-methyl-9a-chloro-cortisoneacetate l6,8-methyl-9a-fiuoro-cortisone acetate.

EXAMPLE III A solution of 1.73 g. of the 2l-acetate of6-dehydrocortisone, described by Mattox et al., in J. Biol. Chem. 197,261 (1952), in 50 cc. of dioxane was treated with 1.0 g. of osmiumtetroxide and kept for 5 days in the dark at room temperature. A slowstream of dry hydrogen sulfide was then introduced into the solutionuntil saturation, and then it was filtered through celite, washing thefilter with dioxane, and the combined filtrate and washings wasevaporated to dryness. The residue was dissolved in methylene chloride,adsorbed in a column of 35 g. of florisil and eluted with methylenechloride-acetone (lzl) and then with acetone, whereupon solid fractionswere obtained. Recrystallization from methanolethyl acetate aiiorded the2l-acetate of 6a,7a-dihydroxycortisone; M.P. 266-269 C. (dec.);EIX]D+1S8O (chloroform) 512? 40 my, log 4.12

into water; the precipitate was collected by filtration,

washed with water, dried and recrystallized from acetonehexane. Therewas thus obtained the free 60:,7oc-dihY- droxy-cortisone. 7

14 EXAMPLE iv W 238 my, log e412 The mother liquor was chromatographedon 6 g. of florisil and the fractions obtained by elution with methylenechloride-acetone (9:1) were recrystallized from acetone, thus furnishingthe 2l-acetate of 1a,2 x-dihydroxy- 6-dehydro-cortisone.

A mixture of 5 g. of d-dehydro-prednisolone, described by Gould et al.,in J. Am. Chem. Soc., 79, 502 (1957), 20 cc. of pyridine and 20 cc. ofpropionic anhydride was allowed to stand at room temperature for 4hours, poured into ice water, the precipitate was collected andrecrystalli'zed from methylene chloride methanol, thus yielding the2l-propionate of 6-dehydro-prednisolone.

Thereafter, by following the procedure described in Example 111, 3 g. ofthe aforesaid 21-propionate of 6- dehydro-prednisolone was treated with3 g. of osmium tetroxide for a period of 3 weeks, to produce finally the21-propionate of 1a,2u,6a,7a-tetrahydroxy-cortisol.

' EXAMPLE VI In accordance with the method of Example 111, the21-benzoate of 9a-fiuoro-prednisolone, described in Patent No. 2,837,541was converted into the 2l-benzoate of afluoro-1a,2a-dihydroxy-cortisol.

EXAMPLE VII In accordance with the method described in Example III, 5 g.of the 16,2l-diacetate of 9oc-fltl01'O-16oc-hYdI'OXY- prednisone,described by Bernstein et al., in J. Am. Chem. Soc., 78, 5693 (1956) wasconverted to the 16,21-diacetate of9afll101'O-1a,2oc,IGa-tIihYdI'OXY-COItiSOIIe.

500 mg. of the above compound was suspended in 20 cc. of acetone,treated under continuous stirring with a few drops of 50% perchloricacid, was stirred for half an hour; after diluting with saturated sodiumchloride solution the precipitate was collected, washed with a littlecold Water, and dried. By chromatography on silica gel there wasobtained the 1,2-acetonide 16,21-diacetate of 9oc-flt101'O-loc,2oc,16u-trihydroxy-cortisone.

EXAMPLE VIII A mixture of 800 mg. of 642,7oc-dli1Yd1'OXY-COIfiSOH6obtained as described in Example III, and 10 cc. of benzaldehyde wastreated with perchloric acid and the product isolated in accordance withthe procedure described for A mixture of 1 g. of the 21-propionate ofl'a,2a,6a,7atetrahydroxy-cortisone prepared as described in Example V,10 cc. of pyridine and 2 cc. of acetic anhydride was allowed to reactovernight to produce, after the usual work up,la,2a,6a,7a-tetraacetoxy-2l-propionoxy-M-pregnen-17a-ol-3,1l,20-trione.

1 EXAMPLE X A mixture of l g. of 6a,7a-dihydroxy-cortisone 2lacetate,obtained as described in Example III, 50 cc. of benzene and 5 g. ofparaldehyde was treated with 5 drops of perchloric acid and kept at roomtemperature for 2 hours. After pouring into 200 cc. of water the organiclayer was separated, washed with 5% aqueous sodium bicarbonate solutionand water, dried over anhydrous sodium sulfate and the benzene wasevaporated. Chromatography of the residue on neutral alumina afforded60;,7a methylenedioxy-cortisone, namely the 6a,7a-formaldehyde-acetal of6a,7u-dihydroxy-cortisone 21-acetate.

EXAMPLE XI In accordance with the method of Example III, the 21- acetateof 6-dehydro-cortisol described by Agnello et al., in J.'Am. Chem. Soc.,79, 1258 (1957), was converted into the ZI-acetate of6a,7a-dihydroxy-cortisol and the acetoxy group of this compound washydrolyzed in ac cordance with the method of hydrolysis described inExample III.

A solution of 500 mg. of the resulting free 6a,7a-dihydroxy-cortisol in50 cc. of cyclohexanone was treated .with 5 drops of perchloric acid,stirred at room tempera- 1.4 g. of the 21-acetate of prednisolone istreated with 1.5 g. of chloranil and 20 cc. of n-amyl alcohol underreflux for 16 hours, cooled and diluted with 60 cc. of ether. The'ethersolution Was successively washed with water, 5% sodium carbonatesolution and again With water, dried over anhydrous sodium sulfate,filtered and evaporated to dryness under reduced pressure.Chromat'ogr'aphy of the residue on neutral alumina furnished theZI-acetate of 6-del1ydro-prednisolone (1,6-bis-dehy- V dro-cortisol).

The latter was then treated by the method described in Example IV, andthere were obtained the 21-acetate of 6e,7a-dihydroxy-prednisolone, and,by chromatography .of the mother liquor, as described in the aforesaidEX- ample IV, the ZI-acetate of 1a,2a-dihydroxy-6-dehydrocortisol.

Saponification of the former of these acetates by the method describedin Example I afiorded the free 6a,7adihydroxy prednisolone.

EXAMPLE XIII Example III is repeated with the 21-acetate of prednisoneto yield 10,2a-dihYd1'OXY-COIHSOD6 ZI-acetate.

Example IV is'repeated with prednisolone to yield 1a,Zor-dlhYdrOXY-COl'fiSOl.

EXAMPLE XV Example IV is repeated with the '21-acetate of prednisoloneto yield la,2u-dihydroxi-cortisol 2l-acetate.

EXAMPLE XVI Example is repeated. with 6-dehydro-prednisone as theStarting material; there is prepared the 21-acetate of the same, and.further treatment by the method described in detail in Example III, fora period of 25 days, and at a temperature of +20 C., yields1a,2a,6a,7a-tetrahydroxy-cortisone 2l-acetate.

EXAMPLE XVII By treating GaJu-dihydroxi-prednisQne 21-acetate by thesaponification step described in Example I, there was obtained 6a,7t-dihydroxy-prednisone.

We claim:

1. A process for producing an a-glycol derivative of a cortical hormone,comprising the steps of reacting a starting compound selected from thegroup of compounds consisting of those having the general formulas:

CHzO R @1520 R C=O C=O wherein R is a member of the group consisting ofhydrogen and the acyl radical of a hydrocarbon carboxylic acid having upto 12 carbon atoms; R is a member of the group consisting of OH: H H

H on, OR X is a member of the group consisting of hydrogen, fluorine,chlorine, and bromine, and Y is selected from the group consisting ofand =0 with osmium tetroxide in mixture with dioxane at a temperature upto room temperature for from about 4 days to several weeks, the molarratio of osmium tetroxide to hormone varying from about 1:1 to about 1:2

and lower, saturating the mixture with gaseous hydrogen sulfide, andisolating the resulting crudle a-glycol product.

2. A compound having the general formula wherein R is a member of thegroup consisting of hydrogen and the acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms; R is a member of the groupconsisting of a V H 011 n H 4 and 17 X is a member of the groupconsisting of hydrogen, fluorine, chlorine, and bromine, and Y selectedfrom the group consisting of and and Z is selected from the groupconsisting of CC and C=C.

3. A compound having the present formula:

CHzOR Y no x H0-- I wherein R is a member of the group consisting ofhydrogen and the acyl radical of a hydrocarbon carboxylic acid having upto 12 carbon atoms; R is a member of the group consisting of H OH; H H 5and H H on, on

X is a member of the group consisting of hydrogen, fluorine, chlorineand bromine, and Y is selected from the group consisting of H and Z isselected from the group consisting of C-C and C=C.

4. A compound having the present formula:

CHzOR Y no x l and =0 wherein R is a member of the group consisting ofhydrogen and the acyl radical of a hydrocarbon carboxylic acid having upto 12 carbon atoms; R is a member of the group consisting of H. OH, I

n H on, X is a member of the group consisting of hydrogen, fluorine,chlorine and bromine, and Y is selected from the group consisting of 5.A compound of the following formula:

( JHrOR if i U 18 wherein R is selected from the group consisting ofhydrogen and a hydrocarbon carboxylic acyl group of up to 12 carbonatoms, R is selected from the group consisting of H on, n 4 .4 n

n n on,

wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of up to 12 carbon atoms, R isselected from the group consisting of H on, n .4 and H H on,

X is selected from the group consisting of hydrogen, fluorine, chlorine,and bromine, Y is selected from the group consisting of =0 and Z isselected from the group consisting of CC and C=C, R and R are eachselected from the group consisting of hydrogen and a hydrocarbon radicalof up to eight carbon atoms and both R and R may form part of a cyclichydrocarbon of up to eight carbon atoms.

7. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of up to 12 carbon atoms, R isselected from the group consisting of n on, n t 5 and n H on,

X is selected from the group consisting of hydrogen, fluorine, chlorineand bromine, Y is selected from the group consisting'of I 7 =0 and E Zis selected from the group consisting of (3-0 and C=C, R and R are eachselected from the group consisting of hydrogen and a hydrocarbon radicalof up to eight carbon atoms and both R and R may form part of a cyclichydrocarbon of up to eight carbon atoms.

20 References Cited in the file of thispatent UNITED STATES PATENTS 1Van der Burg M51. 24, 1959 Angelloet al. v Apr. 14, 1959 OTHERREFERENCES CERTIFICATE OF CORRECTION Patent NO. 3,026,320 March 20 1962Carl Djerassi et al.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 1, lines 26 to 48, the formulas should appear as shown belowinstead of as in the patent:

CH OR (El-120R columns 5 and 6 formula VC should appear as shown belowinstead of as in the patent:

(JH OH C umn 9, lines 25 to 35, the formula should appear as shown belowinstead of as in the patent:

( JH OR column 18, lines 21 to 34, the formula should appearas shownbelow instead of as in the patent:

(IIH OR Signed and sealed this 24th day of July 1962.

(SEAL) Attest:

DAVID L. LADD ERNEST W. SWIDER Attesting Officer Commissioner of Patents

4. A COMPOUND HAVING THE PRESENT FORMULA:
 7. A COMPOUND OF THE FOLLOWINGFORMULA: